Osteogenesis imperfecta

11 Interesting Facts of Osteogenesis imperfecta

  1. Osteogenesis imperfecta is a rare group of inherited disorders of collagen production resulting in low bone mineral density, bone fragility, and frequent fractures
  2. Other clinical features, which depend on the specific mutation, may include blue or gray sclerae, dentinogenesis imperfecta, progressive hearing loss, easy bruising, unstable and lax joints, and muscular weakness
  3. Presentation and course are highly variable, depending on type, gene mutated, and degree of penetrance. Broad phenotypic and genetic basis of disease; therefore, molecular diagnosis can be helpful in predicting severity 
  4. In general, diagnosis is clinical, and molecular analysis is helpful for genetic counseling 
  5. Laboratory testing can rule out other secondary causes of osteopenia, but no test other than genetic analysis is diagnostic of osteogenesis imperfecta 
  6. Obtain radiographs. Suggestive radiographic findings are osteopenia, wormian bones, bowing of long bones, fractures (old, healing, new), and vertebral compression fractures
  7. Bone biopsy can identify most types if the diagnosis is in question 
  8. Multidisciplinary team approach should include supportive care and rehabilitation services
  9. Pamidronate is treatment of choice in moderate to severe cases of Osteogenesis imperfecta; should be used in consultation with a subspecialist 
  10. Fracture management is a balance between minimizing time and extent of immobilization and allowing enough time for healing. Need to minimize secondary disuse osteoporosis (and thus increased risk for future fractures)
  11. People with the Osteogenesis imperfecta have lifelong illness but often live healthy, productive lives 


  • In children, multiple fractures at various stages of healing raise concern for child abuse; skeletal series and DXA can be helpful in differentiating from osteogenesis imperfecta
  • In general, diagnosis can be confirmed by genetic testing; however, no biochemical or genetic test can reliably identify all cases 
    • Some de novo mutations are not included in genetic screening; therefore, a negative molecular screening result does not completely rule out the disease
  • In older, prepubertal children with frequent fractures and osteoporosis, osteogenesis imperfecta can be confused with idiopathic juvenile osteoporosis
    • Diagnosis of idiopathic juvenile osteoporosis is supported by absence of other osteogenesis imperfecta features; if diagnosis is still in question, bone biopsy and genetic sequencing will confirm it
  • Medications that affect bone density or bone healing should be avoided, including corticosteroids; use care with NSAIDs and dose by body weight

Osteogenesis imperfecta is a group of rare heritable disorders associated with abnormal collagen production resulting in low bone mass, bone fragility, and frequent fractures

Most common cause of primary osteoporosis in children

Classification of Osteogenesis imperfecta

  • Type Ι (OMIM #166200) 
    • Mild; nondeforming 
      • Autosomal dominant 
      • Most common type (about 50% of all cases) 
      • Mildest form of disease
      • Decreased type Ι collagen production (about half of normal collagen amount produced)
        • Blue sclerae
        • Dentinogenesis imperfecta is infrequent
        • Presenile deafness is common
        • Ligamentous laxity
        • Fractures can be seen at beginning of ambulation
        • Most fractures are prepubertal and nondeforming
          • Once growth is complete, incidence of fractures diminishes
          • Mild bowing of long bones occurs
          • Vertebral crush fractures are common and can lead to mild scoliosis
        • Aortic regurgitation
        • Normal height to mildly short stature
        • Wormian bones
  • Type ΙΙ (OMIM #166210) 
    • Autosomal dominant
    • Usually perinatally lethal
      • Abnormal type Ι collagen production (structural defects in collagen)
        • Dark sclerae
        • Most infants will not survive past perinatal period
        • Infants are born with multiple intrauterine rib fractures, vertebral fractures, and long bone deformities
        • Pulmonary hypoplasia
        • Central nervous system malformations and hemorrhages
        • Wormian bones
  • Type ΙΙΙ (OMIM #259420) 
    • Usually autosomal dominant, rarely autosomal recessive
    • Most severe form in patients surviving past perinatal period
    • Progressively deforming
      • Abnormal type Ι collagen production (structural defects in collagen)
        • Sclerae are gray at birth but white in adults
        • Dentinogenesis imperfecta and dental malocclusion often present
        • Severe, progressive long bone deformities and bowing
        • Fractures begin in infancy or are present at birth and continue into adulthood
        • Triangular facies and significantly short stature
        • Multiple vertebral compression fractures result in severe scoliosis, kyphosis, and rib cage deformities
        • Malformed growth plates and partially calcified cartilage result in a “popcorn” appearance of metaphyses and epiphyses
        • Elongated vertebral pedicles
        • Decreased ability to ambulate; most patients require a wheelchair
        • Leading cause of death in this group is respiratory compromise secondary to severe scoliosis
  • Type ΙV (OMIM #166220) 
    • Autosomal dominant; cases of new mutation are common
    • Most clinically diverse type, with severe to mild disease
      • Abnormal type Ι collagen production (structural defects in collagen)
        • White or gray sclerae, but any abnormal color tends to fade with increasing age
        • With or without dentinogenesis imperfecta
        • Moderately short stature
        • Joint laxity
        • Bowing of long bones
        • Short femora and humeri are common
        • Variable degree of scoliosis
        • Most children are ambulatory but require walking aids
        • With or without wormian bones
  • Type V (OMIM #610967) 
    • Autosomal dominant
    • Type V accounts for 2% to 3% of cases 
    • Moderate bone fragility
      • Dysregulation of collagen mineralization
        • White sclerae
        • No dentinogenesis imperfecta
        • Mildly to moderately short stature
        • Calcification of forearm intraosseous membrane
        • Radial head dislocation associated with a typical bowing of the forearm is very common
          • Limited supination and pronation of forearm are characteristic
        • Hyperplastic callus formation at fracture sites
          • Lesions may mimic osteosarcoma
        • Radiodense metaphyseal bands in long bone growth plates
        • Mesh-like pattern of bone lamellation
  • Type VI (OMIM #613982) 
    • Autosomal recessive
    • Type VI accounts for 2% to 3% of cases 
    • Moderate to severe
      • White sclerae
      • No dentinogenesis imperfecta
      • Moderately short stature
      • Scoliosis
      • Fish-scale pattern of bone lamellation on histology
      • Accumulation of osteoid on bone-forming surfaces
  • Type VII (#610682) 
    • Autosomal recessive
    • Moderate with variable phenotype; very rare
      • White sclerae
      • No dentinogenesis imperfecta
      • Congenital fractures
      • Rhizomelic shortening of humeri and femora
      • Coxa vara
  • Type VIII (OMIM #610915) 
    • Autosomal recessive
    • Severe and perinatally lethal; very rare
      • White sclerae
      • Severe growth deficiency
      • Extreme skeletal undermineralization
      • Platyspondylia and scoliosis
      • Bulbous metaphyses
      • Long phalanges
  • Type IX (OMIM #259440) 
    • Autosomal recessive
    • Severe, very rare
      • Gray sclerae
      • Progressive deformity
      • Severe growth delay
      • Radiologic features are compatible with types II and III
  • Other types
    • Types numbered X to XVI have entries in Online Mendelian Inheritance in Man, but their clinical relevance is small (very few cases)

Clinical Presentation of Osteogenesis imperfecta

Symptoms of Osteogenesis imperfecta

  • Gross motor delays are commonly reported
  • Hearing loss 
    • 50% of adults with the disease by age 50 years 
    • Prevalence in children with the disease is approximately 5% 
  • Dental abnormalities
    • Dentinogenesis imperfecta occurs in approximately 28% of cases
      • Abnormal dentin results in small, opalescent, deformed teeth
      • Primary dentition is more affected than permanent dentition
    • Malocclusion and delayed eruption of teeth occur in approximately 70% of cases 
  • Ocular changes
    • Blue sclerae, particularly in type I
    • Blue sclerae are more noticeable in infancy
  • Connective tissue features
    • Joint hyperlaxity is common
      • History of frequent joint dislocations
      • Sudden changes in joint appearance or function
      • Double-jointedness or increased mobility of joints
    • Increased capillary fragility
      • History of increased bruising or easy bruising
    • History of hernias
      • Bulging at umbilicus or in inguinal canal
    • Flat feet with little to no arch (pes planus)
      • Clumsiness
  • Skeletal features
    • Frequent bone fractures
      • Fractures from minor trauma or spontaneous fractures
      • Fractures at birth
      • Unusual fracture sites
    • Short stature
  • History of renal calculi
    • Intermittent fluctuating pain in waves starting in the flank and radiating to anterior lower abdominal quadrants
    • Vomiting, dysuria, hematuria
  • Neurologic features
    • Basilar invagination (tip of odontoid process projects above foramen magnum, resulting in obstructive hydrocephalus)
      • Rare but potentially fatal development
      • Headache worse in the morning, dysphagia, blurred or double vision, neck pain
      • Urinary incontinence, muscle weakness, numbness/tingling in hands or feet
    • Cervical spine kyphosis
      • With possible cervical cord impingement
        • Inability to move limbs
  • Cardiovascular features
    • Mitral valve prolapse
      • Chest pain, anxiety, palpitations, fatigue, syncope
  • Pulmonary features
    • Restrictive pulmonary disease resulting from relatively small chest
      • Dyspnea, cough, chest pain
    • Pulmonary hypertension and cor pulmonale
      • Dyspnea, chest pain, cough, hemoptysis
  • Autonomic symptoms
    • Heat/cold sensitivity
    • Increased sweating

Physical examination

  • Head, ears, eyes, nose, and throat
    • Blue sclerae
    • Arcus senilis
      • White, gray, or blue opaque ring in the corneal margin
      • Not associated with hypercholesterolemia
    • Dentinogenesis imperfecta
      • Abnormal dentin resulting in small, opalescent, deformed teeth
        • Chipped, cracked teeth
      • Delayed eruption of teeth
      • Malocclusion
    • Abnormal facies
      • Relatively large cranium and small facial bones
      • Small nose, micrognathia
    • Diminished hearing
      • Mixed conductive and sensorineural
  • Musculoskeletal
    • Delayed gross motor development
    • Fractures
      • Spontaneous fractures
      • Fractures with deformity secondary to minimal trauma
    • Joint hyperlaxity
      • Painless joint movement beyond usual range of motion
    • Joint dislocation
      • Painful joint swelling, deformity, diminished range of motion
    • Bruising
      • Diffuse extensive ecchymoses or contusions
    • Decreased skin elasticity
      • Skin tenting
    • Pes planus
      • Loss of normal arch contour to bottom of foot
    • Pectus excavatum
    • Kyphoscoliosis
    • Genu varum
    • Short stature
    • Muscle weakness
  • Abdominal
    • Hernias
      • Mass palpable in inguinal canal
      • Umbilical hernia may also be present
    • Renal stones
      • Costovertebral angle tenderness
  • Neurologic
    • Basilar invagination (an infolding of the skull case that leads to brainstem distortion and obstructive hydrocephalus)
      • Papilledema
      • Sunsetting (downward deviation of ocular globes)
      • Abnormal extraocular movements
        • Limited upward gaze
        • Sixth nerve palsy (lateral rectus)
          • Inability to turn eye outward
      • Nystagmus
      • Dilated scalp veins
      • Bulging, tense fontanelle; large head
      • Quadriparesis
      • Lower extremity spasticity
        • Increased reflexes and positive Babinski sign
      • Mental status depression is a late finding
      • Cushing triad
        • Hypertension, bradycardia, and irregular respirations
    • Cervical spine kyphosis
      • Sensory or motor disturbances of the upper or lower extremities that can progress to quadriparesis
    • Cerebrovascular accident with rare occurrence of aortic root dissection
      • Horner syndrome
        • Ptosis, miosis, and anhidrosis
      • Hemianesthesia, hemiparesis, and hemiplegia
      • Altered mental status
  • Cardiovascular
    • Mitral valve prolapse
      • Squat-to-stand maneuver produces early systolic click and high-pitched murmur at apex
      • Supine position with leg-raising maneuver (to increase venous return) produces a click later in systole and a shortened murmur
  • Pulmonary
    • Restrictive pulmonary disease
      • Crackles, rhonchi, and diminished aeration
    • Pulmonary hypertension and cor pulmonale
      • Loud fixed split S₂, right ventricular heave, right-sided gallop; left sternal border systolic ejection murmur is worse with inspiration


  • Common causes
    • Autosomal dominant mutation of type Ι collagen gene 
      • Mutations in COL1A1 or COL1A2 gene (collagen, type I, alpha 1 or 2)
        • In type Ι, defect results in diminished production of collagen (quantitative lack)
        • In types II, III, and IV, defect results in structural defects in collagen (qualitative defects) that impair function and interaction with the extracellular matrix
          • Different clinical phenotypic expression ranges from lethal to mildly deforming, depending on specific genetic mutation
    • Mutation in IFITM5 gene (interferon-induced transmembrane protein 5)
      • Type V disease
    • Spontaneous new mutations are common and are responsible for most cases in infants born to unaffected parents 
      • Spontaneous mutations are especially common in type I
  • Less common causes
    • Autosomal recessive mutations
      • Uncommon forms, accounting for approximately 5% to 10% of cases 
      • Mutations have been found affecting critical elements involved in type I collagen secretion and posttranslational modification, as well as signaling and transcription factors involved in osteoblast function
    • Germline mosaicism
      • Very few cases are due to gonadal mosaicism

Risk factors and/or associations

  • Approximately 65% of cases include a positive family history 
    • Autosomal dominant
    • Autosomal recessive
    • Germline mosaicism

How is Osteogenesis imperfecta diagnosed

Diagnostic Procedures

Primary diagnostic tools

  • History and physical examination are diagnostic in most cases
  • Obtain radiographs in all patients (in both suspected and confirmed disease)
    • Obtain initial skeletal series, in consultation with specialist
    • Obtain focused radiographs of cervical, thoracic, and lumbar spine
    • Obtain focused radiographs of bony deformities and possible fracture sites
  • DXA or dual photon absorptiometry (bone mineral density scan)
    • Obtain at diagnosis and with interval monitoring of disease
    • Most helpful in determining if bisphosphonate therapy is indicated, in consultation with specialist
  • Laboratory analysis
    • Serum panels
      • Results are essentially normal in patients with osteogenesis imperfecta
        • Hypercalcuria may be present in approximately 36% of cases, typically in severe forms
        • Alkaline phosphatase level is typically normal unless patient has recently sustained a fracture
      • Occasionally, laboratory tests are indicated to exclude other metabolic causes of osteoporosis
      • Some laboratory tests are monitored regularly as part of disease management and with bisphosphonate therapy
        • Calcium, magnesium, and phosphorus levels; basic metabolic panel
        • Serum 25-hydroxyvitamin D concentration (assessing for vitamin D deficiency)
    • Genetic sequencing/molecular DNA analysis
      • Obtain for all cases
      • Helps direct genetic counseling
    • Biochemical analysis of procollagen and collagen
      • Obtain if genetic sequencing findings are negative and diagnosis is still in question
  • Bone biopsy
    • Obtain if diagnosis is in question or as directed by subspecialist
    • In most cases bone biopsy can identify osteogenesis imperfecta by histomorphologic analysis 


  • Genetic sequencing/molecular DNA analysis
    • Obtain for all cases
    • DNA testing done on blood or saliva is able to identify 90% of cases by locating mutations in COL1A1 or COL1A2 genes
    • Many of the remaining cases can be detected by the less common mutations in CRTAP (cartilage-associated protein), P3H1 (prolyl 3-hydroxylase 1, LEPRE1), and PPIB (peptidylprolyl isomerase B)
  • Biochemical analysis
    • Obtain if genetic sequencing is negative and diagnosis is still in question
    • Dermal biopsy results and protein analysis of cultured fibroblast collagen are positive in approximately 80% of suspected cases 


  • Radiographic findings consistent with this disease include the following:
    • Diffuse osteopenia
    • Gracile long bones with bowing deformities
    • Spiral and transverse long bone fractures
    • Vertebral fractures in 71% of type I cases 
    • Avulsion fractures
      • Olecranon and patella fractures are common
    • Wormian bones in skull 
      • Presence is highly suggestive
      • Present in approximately 60% of cases 
    • Excessive callus formation after fracture
  • DXA or dual photon absorptiometry
    • Obtain at diagnosis and with interval monitoring of disease
    • Scan provides information about bone mineral quantity, not quality
    • Reported as a z score in children compared with age- and gender-matched normative data and plotted on a standard deviation curve, much like a growth chart
    • Reported as T score in adults, with values of −2.5 or lower considered osteoporotic 
    • Results will indicate nonspecific low bone mineral density and/or low bone mass in patients with osteogenesis imperfecta
    • Results can be normal in infants with osteogenesis imperfecta
    • Pediatric software must be used when calculating z score in children to avoid false results
  • Fetal ultrasonography 
    • Abnormalities can be seen on 14-week to 18-week fetal sonograms, raising suspicion for types II and III
      • Increased nuchal translucency
      • Reduced echogenicity of bones (reflecting osteopenia)
      • Multiple fractures of the long bones, ribs, and skull at various stages of healing
      • Bowing of the long bones (with or without shortening)
    • Concern for osteogenesis imperfecta on sonogram leads to definitive intrauterine diagnostic genetic testing


Invasive prenatal genetic screening
General explanation
  • Chorionic villus sampling
    • Preferred technique before 15 weeks’ gestation 
    • Biopsy of placenta is obtained to analyze for abnormalities by fluorescence in situ hybridization or polymerase chain reaction
  • Amniocentesis
    • Technique usually performed after 15 weeks’ gestation 
    • Small amount of fluid containing fetal cells is obtained from fetal sac for analysis
  • Family history of the disease
  • Concern for the disease on fetal sonogram
  • Previous child with the disease born to unaffected parents
  • Infection overlying planned needle insertion site
  • Relative contraindication to fetus, given 1.4% and 1.9% risk of miscarriage with amniocentesis and chorionic villus sampling, respectively 
Interpretation of results
  • Positive result as follows:
    • Finding of abnormal type I collagen via electrophoresis of specimen from chorionic villus sampling, or 
    • Molecular analysis of amniocentesis specimen indicating COL1A1COL1A2CRTAPLEPRE1, or PPIB genetic mutations in fetal DNA 
Bone biopsy
General explanation
  • Sample of bone is obtained under conscious sedation or general anesthesia from anterior iliac crest, then sent for microscopic examination
  • When diagnosis is unclear or in question
    • Unexplained fractures
    • Unexplained osteoporosis
  • Absolute contraindication 
    • Child weighs less than 10 kg
    • Uncorrected severe bleeding disorder (like hemophilia)
    • Uncorrected thrombocytopenia with active bleeding
  • Relative contraindication
    • Patient on anticoagulant therapy
Interpretation of results
  • Histomorphometric analysis of bone biopsy specimen can identify osteogenesis imperfecta

Differential Diagnosis of Osteogenesis imperfecta

Most common

Treatment Goals

  • Maximize mobility and daily life activity 
  • Increase growth and improve bone metabolism
  • Decrease bone pain and number of pathologic fractures

Admission criteria

Children with multiple fractures in whom diagnosis remains uncertain: admit to a safe environment for further work-up, consultation, and management

Criteria for ICU admission
  • Depending on specific clinical scenario, patients with type III and respiratory complications such as pneumonia may need ICU admission owing to potentially low pulmonary reserve and risk for clinical decompensation
  • Admit patients with signs of increased intracranial pressure or focal neurologic findings
  • Admit patients with heart failure from progressive valvular disease or any acute change in aortic root dilatation

Recommendations for specialist referral

  • All patients with osteogenesis imperfecta should have orthopedic consultation
  • All patients with osteogenesis imperfecta should be followed by a metabolic/genetic subspecialist
  • Children with osteoporosis require endocrine consultation and follow-up in a bone health clinic
  • In patients with signs of congestive heart failure, arrange urgent echocardiography, stabilization, and cardiology consultation
  • Multiple other subspecialists typically involved in the interdisciplinary care team
  • All children with multiple fractures and concern for child abuse, but with no definitive diagnosis, require consultation with a child abuse expert

Treatment Options

Multidisciplinary approach, including rehabilitation, orthopedic surgery, and sometimes medical therapy with bisphosphonates, is the foundation of management of Osteogenesis imperfecta

Vitamin D and calcium dietary supplements are commonly used to increase bone density

  • Approximately 25% of patients have low vitamin D levels (serum 25-hydroxyvitamin D)

Decision to begin pharmacotherapy with bisphosphonates depends on clinical severity of disease (eg, frequent fractures, long bone deformities, bone pain) 

  • Adverse effects of bisphosphonate treatment in children must be weighed against the lack of data to suggest that treatment decreases fracture risk or improves clinical parameters (ie, pain, growth, mobility) 
    • Despite relative lack of data to support use of bisphosphonates in children, newer and more rigorous studies are under way, and preliminary results appear promising 
  • Treatment with bisphosphonates should be undertaken in consultation with a genetics specialist or another specialist with experience in the use of bisphosphonates 

Physical therapy, bracing, wheelchairs, and ambulatory assist devices are the cornerstones of supportive care

Surgical management of long bone fractures and deformities includes intramedullary fixation devices, bone lengthening procedures, and fusion of vertebrae 

  • Rods (expandable and nonexpandable) and wire are used rather than nails/plates/screws, because bone is soft

Fracture management is a balance between minimizing time and extent of immobilization and allowing enough time for healing. Need to minimize secondary disuse osteoporosis (and thus increased risk for future fractures)

  • Fractures heal normally in most patients

Medications that affect bone density or bone healing should be avoided, including corticosteroids; use care with NSAIDs and dose by body weight

Drug therapy

  • Bisphosphonates
    • Should be used in consultation with a specialist with experience in the use of bisphosphonates
    • For patients with significant bone pain, frequent fractures, very low bone mineral density, significant mobility deficits, and growth deficiency
    • Improve bone mineral density
      • Pamidronate
        • Pamidronate Disodium Solution for injection; Children and Adolescents: Off-label cyclic dose: 1.5 to 3 mg/kg/cycle IV infusion, divided in 3 equivalent doses that are given over 4 hours once daily for 3 days. The cycle is repeated every 4 to 6 months. A second study confirmed that 1 mg/kg/day IV infusion (over 4 hours) once daily for 3 days and repeated cyclically every 4 months is efficacious. Supplement with adequate calcium and vitamin D intake.
      • Alendronate
        • Off-label use
        • Alendronate Sodium Oral tablet; Adult males: 10 mg PO once daily. Supplement calcium and vitamin D if dietary intake is inadequate.
      • Risedronate 
        • Off-label use
          • Risedronate Sodium Oral tablet; Adults: 5 mg PO once daily. Supplement calcium and vitamin D if dietary intake is inadequate. Reevaluate periodically. For those patients at low risk for fracture, consider stopping risedronate after 3 to 5 years.

Nondrug and supportive care

  • Wheelchair or other ambulation aids 
  • Bracing 
    • Early intervention with occipitocervical bracing in patients who develop basilar invagination can delay the progression
    • Leg braces
    • Back braces to prevent vertebral fractures have been used but are not commonly indicated because of risk for damage to anterior chest and rib cage
  • Rehabilitation 
    • Physical therapy
      • Weight-bearing exercises and hydrotherapy
      • Strengthening of the trunk muscles and extremities may be used to decrease back pain, improve breathing capacity, and improve trunk stability for sitting 
    • Occupational therapy
      • Indicated for patients with upper extremity deformities, to assist with activities of daily living and self-care
  • Surgical management 
    • Specific treatment of fractures depends on type of fracture and age of patient


  • Osteoporosis
    • Interval monitoring DXA recommended; frequency of monitoring is not universally established and depends on type and severity of disease
    • Skeletal radiographs and bone mineral density assessments are monitored in conjunction with orthopedic recommendations
      • Perform more frequent monitoring in children receiving bisphosphonate therapy
    • Aortic root dilatation and valvular disease
      • Perform interval monitoring echocardiography and ECG; frequency of monitoring is not universally established and depends on type and severity of disease
    • Pulmonary function
      • Perform interval spirometry in patients with moderate to severe osteogenesis imperfecta; frequency of monitoring is not universally established and depends on type and severity of disease
    • Hearing
      • Obtain audiology evaluation every 3 to 5 years after adolescence 
    • Laboratory monitoring with bisphosphonate therapy
      • Obtain calcium, magnesium, and phosphorus levels; basic metabolic panel; and serum 25-hydroxyvitamin D concentration (assessing for vitamin D deficiency), in conjunction with subspecialist recommendations. Frequency of monitoring is not universally established and depends on severity of disease and response to bisphosphonate therapy
    • Vision
      • Perform annual ophthalmologist examination and vision screening 


  • Skeletal
    • Fractures
      • Fractures have been reported from blood pressure cuffs in these patients 
    • Dislocations
    • Cervical spine kyphosis and scoliosis develop with severe forms of disease
    • Bone pain
      • Bone pain from deformities and degenerative lesions is common
      • It is a myth that children with osteogenesis imperfecta have decreased sensitivity to pain
  • Gastrointestinal: constipation is common
  • Ocular: high incidence of myopia
  • Otologic: hearing loss is common by third decade of life
  • Pulmonary
    • Restrictive pulmonary disease and recurrent pneumonia
      • Secondary to severe scoliosis and vertebral crush fractures
      • Primary lung problems (eg, asthma, pneumonia) are more severe than in the general population
        • Lung collagen abnormalities contribute to high pulmonary complication risk
      • Restrictive pulmonary disease can lead to pulmonary hypertension and cor pulmonale
  • Autonomic
    • Some patients report heat/cold sensitivity and increased sweating
  • Aortic and cardiac
    • Aortic root dilation
      • Most patients develop some degree of aortic root dilation with years of disease
      • Usually asymptomatic
      • Patients are predisposed to aortic aneurysms, particularly of aortic root
      • Aortic dissection is rare
      • Progression to congestive heart failure is rare
    • Cardiac valvular disease
      • Aortic valvular disease and mitral valve prolapse can develop
  • Renal stones (in about 20% of patients) 
  • Sleep apnea
  • Hydromyelia
    • Damage to spinal cord and nerves from severe scoliosis or kyphosis is a potential complication with progression of disease
  • Basilar invagination caused by large head and soft bones of cervical spine
    • Basilar invagination is an infolding of the skull base (tip of odontoid process gradually projects above foramen magnum), resulting in brainstem distortion and obstructive hydrocephalus
    • Rare complication of severe forms of disease (eg, types III and IV) and can result in posterior fossa compression syndrome (increased intracranial pressure and hydrocephalus)
  • Death
    • Type II is lethal at birth or in the perinatal period


  • Prognosis is variable depending on the particular genetic defect. Moreover, extremely variable penetrance exists for each genetic defect, resulting in a wide variety of phenotypical presentations for the same mutation
  • Most people with the disease live healthy, productive lives but do have lifelong medical issues 
  • Life span varies by type and within type
    • Mild to moderate forms do not affect life expectancy
    • Type III is progressively deforming; patients have life expectancy of more than 50 years if they do not die of the cardiac or pulmonary complications associated with disease progression 
      • Clusters of mortality in type III occur in early childhood, teen years, and fifth decade, resulting from pulmonary complications 


At-risk populations

  • Persons with family history of the disease
  • Persons with frequent fractures 
    • Indications for further bone health evaluation include the following:
      • 1 vertebral compression fracture in the absence of significant trauma
      • 2 or more long bone fractures by age 10 years
      • 3 or more long bone fractures by age 19 years

Screening tests

  • Genetic screening 
    • Recommended for parents of any child born with the disease, before any future pregnancies
    • Information obtained is used for genetic counseling before any future pregnancies
  • Amniocentesis and chorionic villus sampling 
    • Testing of fetus is indicated with any abnormal finding on prenatal sonogram that is suggestive of the disease
    • Prenatal testing should be considered in any offspring who has an affected parent with the disease
    • If fetus has this diagnosis, then delivery precautions should be taken, given the fragile bone state; elective cesarean delivery may be considered
    • Prenatal testing can determine what type a fetus has, which can guide family about potential natural course


  • Genetic counseling
    • Genetic counseling is recommended for any woman with the disease who is planning pregnancy 
    • Genetic counseling is imperative for any asymptomatic parents of a child with the disease, before any future pregnancies 
      • Determine whether parents are recessive carriers of relevant mutations
      • Determine whether 1 parent has undiagnosed disease
      • Determine whether 1 parent is a mosaic carrier of a dominant mutation


Krakow D: Skeletal dysplasias. Clin Perinatol. 42(2):301-19, viii, 2015 Reference


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